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Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53
Author(s) -
Lee ChungHan,
Inoki Ken,
Karbowniczek Magdalena,
Petroulakis Emmanuel,
Sonenberg Nahum,
Henske Elizabeth Petri,
Guan KunLiang
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601900
Subject(s) - pi3k/akt/mtor pathway , biology , cancer research , tsc2 , rptor , autophagy , carcinogenesis , dna damage , cell growth , suppressor , tsc1 , apoptosis , mutant , microbiology and biotechnology , signal transduction , dna , genetics , cancer , gene
Miscoordination of growth and proliferation with the cellular stress response can lead to tumorigenesis. Mammalian target of rapamycin (mTOR), a central cell growth controller, is highly activated in some malignant neoplasms, and its clinical implications are under extensive investigation. We show that constitutive mTOR activity amplifies p53 activation, in vitro and in vivo , by stimulating p53 translation. Thus, loss of TSC1 or TSC2, the negative regulators of mTOR, results in dramatic accumulation of p53 and apoptosis in response to stress conditions. In other words, the inactivation of mTOR prevents cell death by nutrient stress and genomic damage via p53. Consistently, we also show that p53 is elevated in TSC tumors, which rarely become malignant. The coordinated relationship between mTOR and p53 during cellular stress provides a possible explanation for the benign nature of hamartoma syndromes, including TSC. Clinically, this also suggests that the efficacy of mTOR inhibitors in anti‐neoplastic therapy may also depend on p53 status, and mTOR inhibitors may antagonize the effects of genotoxic chemotherapeutics.